The invention relates to neurodegenerative disease.
The role of the .beta.-amyloid peptide (Glenner et al., 1984, Biochem. Biophys. Commun. 120:88-890) in the pathogenesis of Alzheimer's disease is highly controversial. The .beta.-amyloid protein is derived from the transmembrane amyloid precursor protein (APP; Kang et al., 1987, Nature 325:733-736). While deposition of .beta.-amyloid is an invariant feature of Alzheimer's disease, research to date has not elucidated the relationship between .beta.-amyloid plaque deposition and the behavioral and neuropathological features that characterize clinically defined Alzheimer's disease. Studies in vitro have demonstrated that the peptide has both neurotoxic and neurotropic activity, including toxicity in primary cultures of human cortical neurons and dissociated neurons from adult mice. The results of studies in vivo have been less clear.
.beta.-amyloid synthetic peptides, in a variety of sequence lengths and in a number of vehicles, have been administered to the brains of both primates and rodents resulting in only minimal specific neurodegeneration. When administrated by acute injection into either rodents or primates, .beta.-amyloid has failed to consistently produce Alzheimer-specific pathological alterations. Damage induced by the delivery system has been extensive, making it difficult to assess whether amyloid caused specific effects.
A chronic infusion paradigm, in which a mixture of .beta.-amyloid and heparan sulfate proteoglycans are infused, has been reported to produce Congo red positive plaques in rats. Although the .beta.-amyloid peptide of Alzheimer's disease has been implicated in the disease process, the mechanism by which amyloid may contribute to neurodegeneration is not understood.